Menin inhibitors for acute myeloid leukemia: latest updates from the 2023 ASH Annual Meeting

Recent developments in menin inhibitors for relapsed or refractory acute myeloid leukemia (AML) were highlighted at the 2023 ASH Annual Meeting. Notably, revumenib showed promising efficacy, achieving a 100% ORR when combined with decitabine/cedazuridine and venetoclax. These findings underscore the potential of menin inhibitors in transforming AML treatment, particularly in genetically defined subgroups, offering hope for improved patient outcomes. Ongoing studies, like KOMET-008, further explore the synergistic potential of menin inhibitors in combination regimens, shaping future AML management strategies.


Revumenib (SNDX-5613)
Revumenib, a selective Menin inhibitor, has shown substantial efficacy, particularly for AML patients with KMT2A rearrangements (KMT2Ar).Issa et al. reported significant outcomes in a Phase I/II trial where 7 evaluable patients with relapsed or refractory(r/r) AML characterized by KMT2A rearrangements were assessed.Revumenib combined with decitabine/cedazuridine and venetoclax achieved a 100% overall response rate (ORR), with all evaluated patients attaining morphological remission [3].

To the editor
Acute myeloid leukemia (AML) remains challenging, particularly subtypes characterized by genomic instability, such as KMT2A rearrangement and NPM1 mutations [1,2].Current treatment regimens, including chemotherapy and targeted therapies, often lead to limited longterm success and significant toxicity.Menin inhibitors have emerged as a promising therapeutic approach, particularly for AML subtypes with specific genetic abnormalities such as KMT2A rearrangements and NPM1 mutations (Table 1).Here we synthesize findings from the 2023 ASH Annual Meeting, focusing on the efficacy complete response (CR), and five achieved or sustained measurable residual disease (MRD) negativity [4].

DSP-5336
DSP-5336, an investigational oral menin inhibitor, targets the menin and MLL protein interaction.The dose escalation portion of the DSP-5336 study consists of two parallel arms (Arm A: without concomitant anti-fungal azole therapy; Arm B: with concomitant azole therapy).Among six MLLr patients treated, one achieved a five-month CR, another maintained a morphologic leukemia-free state, and one had stable disease.For four NPM1 patients, treatment resulted in stable disease [9] (Table 2).

BMF-219
BMF-219, a pioneering covalent menin inhibitor, is under evaluation in the COVALENT-101 study (NCT05153330), which included adults with r/r acute leukemia ineligible for standard therapy.Among the efficacy evaluable population, two out of five patients achieved complete remission [10] (Table 2).

JNJ-75,276,617
In the Phase 1 study of JNJ-75,276,617(NCT04811560), conducted by Jabbour et al., this menin-KMT2A inhibitor was evaluated in adult patients with r/r AML harboring KMT2A or NPM1 mutations.From the 58 patients enrolled, 97% had r/r AML, and 3% had ALL, adverse events were manageable(Table 2).The clinical efficacy was highlighted by a 63% reduction in bone marrow disease burden.At the highest dose tested, the ORR was 50%, the time to response ranged from 1.0 to 3.3 months [11] (Table 2).

Safety and adverse events
The safety profile of menin inhibitors was manageable.
Common adverse events included gastrointestinal symptoms, cytopenias, and, less frequently, differentiation syndrome, which were generally reversible with dose adjustments or supportive care [6] (Table 2).
Traditional AML treatments like intensive chemotherapy and HSCT often lead to significant toxicities and limited efficacy, especially in relapsed/refractory cases.Menin inhibitors have shown in clinical trials to induce remission in heavily pretreated populations with a more manageable safety profile.They present fewer severe adverse events and effective management of differentiation syndrome, making them a significant advancement in AML management.
The 2023 ASH Annual Meeting highlighted the transformative potential of menin inhibitors, especially for genetically defined subgroups.Future research should explore their synergistic potential with other therapeutic agents, such as hypomethylating agents and BCL-2 inhibitors, to enhance treatment efficacy and assess long-term response durability.
Further, Zucenka et al. discussed the outcomes of Revumenib maintenance therapy post-hematopoietic stem cell transplant (HSCT) in the AUGMENT-101 study.Of 131 treated patients, nine resumed Revumenib post-transplant, with treatment durations ranging from 23 to 588 days.Notably, six of the nine patients who resumed Revumenib post-transplant maintained

Table 1
Summary of menin inhibitors